Adults with major depressive disorder (MDD) often show glucocorticoid resistance evidenced by abnormal dexamethasone suppression test (DST), high baseline cortisol concentrations at all times of the day, and failure to develop Cushingoid features. In order to gain insight into this phenomenon and its relationship to MDD, this proposal will examine in detail the glucocorticoid cell interaction in vitro in two representative peripheral cell types, fibroblasts and mononuclear leukocytes (MN-WBC), from adults with MDD, ages 18-60 years. For comparison, cells will be taken from both normal controls and psychiatric patients without depressive symptomatology. All patients will be categorized psychiatrically using the Schedule for Affective Disorder and Schizophrenia (SADS) interview and Research Diagnostic Criteria (RDC). The patient's glucocorticoid secretion status will be documented with the circadian basal secretion of cortisol using the constant withdrawal pump technique and the DST. The specific glucocortioid cell interactions which we propose to study are the following: 1) the binding of glucocorticoid to its receptor; 2) the steps between this initial receptor binding and the activation of the transcription event initiated by the glucocorticoid-receptor-acceptor complex; 3) selected post- receptor functions. A preliminary study of adults with MDD suggests that the initial glucocorticoid receptor binding is normal but that there is an alteration in the overall glucocorticoid mediated cell function. This abnormality is most clearly demonstrated in the MN-WBC from MDD patients as an increased ACTH production and a reduced ability of dex to inhibit that production compared to MN-WBC from control groups. These abnormalities in glucocorticoid-cell interaction will be reexamined with MN-WBC from the MDD patients when they are in remission. Information about these abnormalities should increase our understanding of the relationship between MDD and peripheral glucocorticoid receptor physiology and will help to define the hypothalamic pituitary adrenal axis defect associated with MDD. Also these abnormalities may provide a new biological marker for MDD.